Home' Australian Pharmacist : Australian Pharmacist April 2013 Contents Australian Pharmacist April 2013 I ©Pharmaceutical Society of Australia Ltd. 71
EVIDENCE BASED MEDICINE IN ACTION
By Dr Luke Bereznicki & Dr Ron Castelino
In the first article in this series, we gave an overview of the basics of
evidence-based medicine and in particular, the process to work through to
answer clinical questions. The next three articles in this series will focus in
detail on understanding the strength of each level of evidence by defining
study designs and their characteristics.
In this article we will focus on randomised
controlled trials (RCTs).
What are RCTs?
RCTs have been a key driver in the
evolution of EBM and advances in medical
science over the past 50 years. Clinical
trials are prospective ('forward looking')
experiments involving human subjects
who receive treatment to evaluate
The advantage of experimental studies
like RCTs is that the investigators are
in control of who is exposed and not
exposed to the intervention under
investigation. In observational designs
investigators study people as they find
them, and subjects who receive an
intervention or treatment may differ from
people who do not in a number of ways,
which can confound the outcome.
The critical aspect of RCTs is that the
allocation to treatment (often an 'active'
treatment or a placebo) is determined
by chance, and not the presence or
absence of other variables, or the choice
of the investigator. This helps to ensure
that confounding factors that affect
the outcome of interest are minimised.
The influence of any confounding effects
is also minimised by randomising large
groups of patients.
Why are they important?
A key underlying theme in the practice
of EBM is -- understanding the hierarchy
of evidence and the inherent limitations
of different study designs. RCTs appear
Dr Luke Bereznicki is Senior Lecturer in
Pharmacy Practice and Acting Head
of School at the Tasmanian School of
Pharmacy. Dr Ron Castelino is a Lecturer
in Therapeutics and Pharmacy Practice
at the School of Pharmacy, University
at the top of the hierarchy of trial
designs because they are the most
scientifically rigorous way of investigating
whether a cause and effect relationship
exists between a treatment and an
outcome. It follows that they can then
be used as the basis for assessing the
cost-effectiveness of a given treatment.
The results of several RCTs comparing the
effectiveness of treatments at achieving
the same outcome can be pooled using
meta-analysis (statistical methods of
combining evidence used in a systematic
review), which provides the highest
level of evidence for the comparison of
therapies to achieve a given outcome.
What are the critical features
The most important features of RCTs are:
• the selection of endpoints
• random allocation to treatment groups
• the intention to treat principle.
Ethically, clinical trials should only be
conducted in areas of uncertainty,
and should only continue so long as
uncertainty remains. Therefore, RCTs
usually need to contain a standard
treatment arm. If a standard therapy
exists, it would be unethical to include a
therapy that is known to be less effective
than another treatment. However, the
concept of 'standard therapy' may vary
geographically, and between individuals,
and where significant uncertainty
remains, a clinical trial may be justified
based on the local clinical practice.
The primary endpoint
Well designed RCTs will focus on a
single major objective (the primary
outcome) with all other outcomes
treated as secondary. The selection of
the primary endpoint is a critical part
of the experimental design, because it
dictates the size of the groups required
to demonstrate a change in the outcome
(if a change exists). The use of multiple
primary endpoints suggests that
investigators have biased the results
of the study by determining endpoints
after the study has been completed.
Most scientific journals require that RCTs
are registered in an appropriate trial
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